Neuropeptide Y (NPY) is a peptide consisting of 36 amino acids. In recent years it has been established that NPY is an important co-transmitter in the peripheral sympathetic nervous system.
It has been postulated (see Pharmacological Reviews (1996) 48, 113) that the effects of sympathetic nerve activation are not only due to the neuronal release of noradrenaline but may also be the result of a simultaneous release of NPY from the sympathetic nerve terminal.
Released NPY is known to elicit marked constriction of blood vessels in both the heart (coronary arteries) and in most peripheral organs. This vasoconstrictive effect of NPY is believed to be mediated by a receptor sub-type known as Y.sub.1.
Released NPY may also act on autonomic nerve endings to inhibit the release of neurotransmitters and, in doing so, reduce the cardiac vagal tone as a result of decreased acetylcholine release. This effect of NPY is believed to be mediated by a receptor sub-type known as Y2.
Other NPY-receptor sub-types, including the Y.sub.3, Y.sub.4, Y.sub.5 and Y6 sub-receptors, have been identified. The precise functions of these sub-receptors have not been identified in any detail, but the Y.sub.5 sub-receptor is thought to be involved in feeding and eating regulation (see Exp. Opin. Invest. Drugs, 6, 437 (1997)).
Increased plasma concentrations of NPY have been found in several cardiovascular diseases including angina pectoris, myocardial infarction and hypertension. Further, emotional stress has been shown to cause a significant increase in plasma NPY levels (see Circulation (1994) 90, I-268, Abstract No. 1445). Such observations suggest a significant pathogenic role for NPY in myocardial ischemic heart disease and hypertension. Moreover, by causing coronary vasoconstriction and reduced vagal tone, NPY may predispose a patient to ventricular fibrillation and sudden cardiac death.
Effective NPY antagonists would therefore be expected to be useful in the treatment of inter alia cardiovascular diseases.